A clinical trial for psoriasis with novel single-cell genomic techniques to understand regulatory immunity behind long-term disease remission off drug induced by short-term IL-23 inhibition

使用新型单细胞基因组技术进行银屑病临床试验，以了解短期 IL-23 抑制诱导的药物长期疾病缓解背后的调节免疫

• 批准号: 10340103
• 负责人: Jaehwan Kim
• 金额: $ 16.89万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10340103
• 关键词: Anatomy; Antibodies; Antigen-Presenting Cells; Biological; Biological Markers; Biological Products; Biopsy; Biopsy Specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Communication; Cells; Chromatin; Clinical; Clinical Trials; Data; Dendritic Cells; Digestion; Disease; Disease Progression; Disease remission; Dose; Enzymes; Epidermis; FOXP3 gene; Gene Expression; Genomics; Goals; Hour; Human; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immunity; Immunobiology; Injections; KLRB1 gene; Lesion; Machine Learning; Mentors; Messenger RNA; Microfluidics; Molecular; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural Killer Cells; Outcome; Pathogenicity; Pathologic; Patients; Pharmaceutical Preparations; Phase; Phenotype; Psoriasis; Public Health; Recurrence; Regulation; Regulatory T-Lymphocyte; Research; Skin; T-Lymphocyte; Techniques; Testing; base; cell type; chronic inflammatory disease; clinical application; combinatorial; cytokine; drug clearance; genetic signature; genomic data; healthy volunteer; indexing; innovation; interleukin-23; keratinocyte; melanocyte; novel; predictive modeling; prevent; programs; restoration; single-cell RNA sequencing; skin disorder; transcriptome; transcriptome sequencing

Although highly effective, biologics targeting IL-23/Th17 axis should be continuously injected to suppress recurrence of psoriasis. My long-term goal is to cure psoriasis without recurrence guided by personal immune tolerance. The overall objectives in this application are to (i) identify regulatory immune cell interactions induced by anti-IL-23p19 antibody administration in the skin of patients whose psoriasis is cleared without recurrence and (ii) develop pre-treatment predictive models for psoriasis patients that anticipate disease recurrence after short-term anti-IL-23p19 antibody injection. The central hypothesis is that IL-23p19 inhibition promotes regulatory immune cells in psoriasis patients whose disease is cleared without recurrence, and their pre-treatment single-cell immune signatures are different from those of patients whose disease recurs. The rationale for this project is that molecular evidence of immune tolerance induction by IL-23p19 inhibition in human skin is likely to offer a strong clinical framework whereby new strategies to prevent recurrence of chronic inflammatory diseases can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) Testing the hypothesis that regulatory immune cell interactions are promoted by short-term anti-IL-23p19 antibody administration in the skin of psoriasis patients whose disease becomes clear without recurrence; and 2) Developing predictive models with pretreatment skin biopsy single-cell genomic data that anticipate long-term disease clearance off drug after short-term anti-IL-23p19 antibody administration. To achieve the specific aims, we have recently developed two innovative complementary single-cell approaches to obtain gene expression profiles of heterogeneous immune cells from psoriasis and control skin without enzyme digestion. The first single-cell experimental approach is microfluidic partitioning of emigrating cells from human skin after 48-hour incubation in culture medium without enzyme digestion, which empowers single-cell transcriptomic profiling of heterogeneous immune cells and keratinocytes in different layers of epidermis under ex vivo condition. The second single-cell experimental approach is Combinatorial indexing RNA sequencing, developed by the co-mentor of the proposal, which enables co-profiling transcriptome and single-cell chromatin accessibility. At the completion of the proposed research, our expected outcomes are to have novel single-cell genomic techniques to study immune cell interactions in human skin, defined single-cell gene signatures of regulatory immune cells that are promoted by anti-IL-23p19 antibody administration in psoriasis skin, and the ability to elucidate how pathologic immunity is suppressed at the single-cell level by highly effective biologics. We also expect to have pre-treatment biomarkers that can predict long-term disease clearance off drugs after short-term anti-IL-23p19 antibody administration.

虽然非常有效，但针对 IL-23/Th17 轴的生物制剂应持续注射 抑制牛皮癣的复发。我的长期目标是治愈牛皮癣而不复发 个人免疫耐受。本申请的总体目标是 (i) 识别监管免疫 银屑病患者皮肤中施用抗 IL-23p19 抗体诱导的细胞相互作用 被清除而不会复发，并且（ii）为银屑病患者开发治疗前预测模型， 预测短期抗 IL-23p19 抗体注射后疾病复发。中心假设是 IL-23p19 抑制可促进疾病被清除的银屑病患者的调节性免疫细胞 无复发，治疗前单细胞免疫特征与患者不同 谁的疾病复发。该项目的基本原理是免疫耐受的分子证据 通过抑制人类皮肤中的 IL-23p19 进行诱导可能会提供一个强大的临床框架，从而使新的 可以制定预防慢性炎症疾病复发的策略。中心假设 将通过追求两个具体目标来进行测试：1）测试调节性免疫细胞的假设 在银屑病患者皮肤中短期施用抗 IL-23p19 抗体可促进相互作用 疾病已明确且未复发； 2) 通过预处理开发预测模型 皮肤活检单细胞基因组数据可预测药物治疗后长期疾病清除 短期抗IL-23p19抗体施用。为了实现特定目标，我们最近开发了 两种创新的互补单细胞方法来获得异源基因表达谱 来自牛皮癣的免疫细胞无需酶消化即可控制皮肤。第一个单细胞实验 方法是在 48 小时孵育后对来自人体皮肤的迁移细胞进行微流体分离 在没有酶消化的培养基中，这使得单细胞转录组分析成为可能 离体条件下表皮不同层的异质免疫细胞和角质形成细胞。 第二种单细胞实验方法是组合索引 RNA 测序，由 该提案的共同导师，该提案能够对转录组和单细胞染色质可及性进行共同分析。 在完成拟议的研究后，我们的预期结果是获得新型单细胞 研究人类皮肤免疫细胞相互作用的基因组技术，定义单细胞基因特征 在银屑病皮肤中施用抗 IL-23p19 抗体可促进调节性免疫细胞的生长， 以及阐明如何通过高效的方法在单细胞水平上抑制病理免疫的能力 生物制剂。我们还期望有可以预测长期疾病清除的治疗前生物标志物 短期抗 IL-23p19 抗体给药后停药。